Histological markers of neonatal asphyxia

Transcription

www.jpnim.com Open Access eISSN: 2281-0692
Journal of Pediatric and Neonatal Individualized Medicine 2014;3(2):e030275
doi: 10.7363/030275 Received: 2014 Sept 30; accepted: 2014 Oct 16; published online: 2014 Oct 21
Review
Histological markers of neonatal
asphyxia: the relevant role of
vascular changes
Clara Gerosa1, Daniela Fanni1, Melania Puddu2, Giorgia Locci1, Eleonora
Obinu1, Vassilios Fanos2, Gavino Faa1
1
Department of Surgical Sciences, Section of Pathology, University of Cagliari, Cagliari, Italy
2
Neonatal Intensive Care Unit, Neonatal Pathology, Puericulture Institute and Neonatal Section, AOU and
University of Cagliari, Cagliari, Italy
Proceedings
Proceedings of the International Course on Perinatal Pathology
(part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014)
Cagliari (Italy) · October 25th, 2014
The role of the clinical pathological dialogue in problem solving
Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken
Abstract
Perinatal asphyxia is one of the leading causes of morbidity and mortality
in the perinatal period, with 4 million neonates suffering annually from
birth asphyxia. Tissue hypoxia can cause several pathological changes in
multiple organs, hypoxic-ischemic encephalopathy (HIE) representing one
of the most severe consequences in the newborn, occasionally leading to
the insurgence of the multi-organ dysfunction syndrome. The pathological
diagnosis of neonatal asphyxia is complex, histological markers of tissue
hypoxia often overlapping with pathological changes due to other etiologies.
This work is aimed at summarizing the most important pathological markers
of asphyxia occurring in a newborn in the different organs. The endothelial
lesions (swelling, apoptosis, detachment and loss of the endothelial barrier)
in our experience, represent the most relevant pathological changes induced
by hypoxia in all the organs. The finding of increased hepatic hemopoiesis
represents one of the most important markers of chronic tissue hypoxia. In
conclusion, the accurate histological study of all the organs in every case of
perinatal asphyxia may allow, in expert hands, perinatal pathologists to give
important data to neonatologists for reaching, together, a complex clinical/
pathological diagnosis, able to explain the clinical course in the majority of
asphyxiated newborns undergoing multiple organ dysfunction.
1/11
www.jpnim.com Open Access
Journal of Pediatric and Neonatal Individualized Medicine • vol. 3 • n. 2 • 2014
Keywords
Neonatal asphyxia, endothelial dysfunction, MOF,
newborn, tissue hypoxia.
Corresponding author
Gavino Faa, Department of Surgical Sciences, Division of Pathology,
University of Cagliari, Cagliari, Italy; email: [email protected].
How to cite
Gerosa C, Fanni D, Puddu M, Locci G, Obinu E, Fanos V, Faa G.
Histological markers of neonatal asphyxia: the relevant role of vascular
changes. J Pediatr Neonat Individual Med. 2014;3(2):e030275. doi:
10.7363/030275.
Introduction
Tissue hypoxia represents a clinical problem
frequently observed in newborns admitted to neonatal
intensive care unit (NICU), in the clinical setting of
placental, pulmonary and cardiac diseases. Perinatal
asphyxia is one of the leading causes of morbidity and
mortality in the perinatal period, with 4 million neonates
suffering annually from birth asphyxia [1]. Hypoxia
can cause several pathological changes in multiple
organs, hypoxic-ischemic encephalopathy (HIE)
representing one of the most severe consequences in
the newborn, occasionally leading to the insurgence
of the multi-organ dysfunction syndrome [2]. The
clinical diagnosis of perinatal asphyxia is mainly based
on the evidence of neurological and cardiorespiratory
depression associated with acidemia. Recently, the
analysis of the urinary metabolomic profile has been
proposed as a new tool for a more in depth diagnosis
and for a better prognosis in asphyxiated neonates [1].
The pathological diagnosis of neonatal asphyxia is
much more complex, histological markers of asphyxia
often overlapping with pathological changes due to
other etiologies.
This work is aimed at summarizing the most
important pathological markers of asphyxia occurring
in a newborn in the different organs, helping
pathologists involved in autopsy of an asphyxiated
neonate to find their way for an in-depth clinicalpathological diagnosis. Moreover, we will try to
correlate the most important data on the molecular
pathways involved during neonatal hypoxia with the
histological data, trying to remove the gap actually
existing between our knowledge of molecular events
taking place during asphyxia and their histological
counterpart.
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Molecular mechanisms
tissue damage
of
hypoxia-induced
The most important mediators in cellular oxygen
homeostasis are represented by hypoxia-inducible
factor-1 (HIF-1) and -2 (HIF-2), two hydroxilases
that facilitate oxygen delivery in physiology and
adaptation to oxygen deprivation in the clinical
setting of asphyxia [3]. HIF-1 and HIF-2 are both
transcriptional factors (TF) that increase transcription
of multiple specific hypoxia-responsive genes [4].
Differential roles have been described regarding the
target genes regulated by HIF-1 and HIF-2, only
occasionally the action of both TFs overlapping [5].
HIF-1 regulates glycolytic genes and in particular
insulin-like growth factor 2 [6], and it is also
involved in the regulation of adipogenesis, through
the transcriptional regulation of the DEC1/Stra13
gene [7]. HIF-2 is involved in the regulation of
angiogenesis, being the main regulator of vascular
endothelial growth factor (VEGF). HIF-2 also
regulates hemopoyesis through the transcriptional
regulation of the erythropoietin (EPO) gene, and iron
metabolism through the transcriptional activation of
the transferring receptor gene [8], whereas HIF-1
regulates the expression of the transferring gene [9].
In conditions of tissue hypoxia, HIF-2 also interferes
on iron metabolism by suppressing the hepatocytic
production of hepcidin, resulting in increased iron
uptake and transport in the intestinal epithelium
[10]. A specific HIF-2 target is Oct4: through
its activation, HIF-2 regulates stem cell function
and embryonic development [11]. In addiction to
acting as TFs, HIF-1 and HIF-2 regulate important
intracellular pathways and modulate fundamental
biological processes through direct protein-protein
interaction. HIF-1 induces cell cycle arrest by
functionally counteracting the proto-oncogene Myc
[12]. By interacting with the protein product of the
NOTCH gene, HIF-1 modulates NOTCH signaling,
maintaining the undifferentiated state in stem cells
during development [13].
Histological markers of hypoxia
Vascular changes
Blood vessels, and in particular endothelial
cells, probably represent the most important target
of neonatal asphyxia. From a practical point of
view, arterial and venous changes should represent
the focus of the histological examination of all the
organs in every case of perinatal asphyxia. The
Gerosa • Fanni • Puddu • Locci • Obinu • Fanos • Faa
main histological changes detectable in every organ
are here reported.
Arteriolar vasodilatation
Vasodilatation of arterioles represents one
of the most important changes induced by
hypercapnia. This effect, easily recognized at
histology by the presence of enlarged arterioles
containing red blood cells within their lumen, is
mainly due to the disactivation of mitochondrial
ATP-sensitive K+ channels, which results in
arteriolar vasodilatation [14].
Endothelial cells
Major changes are constantly observed in
endothelial cells when tissue hypoxia occurs
(Fig. 1). The molecular pathway leading to
hypoxia-induced endothelial damage is probably
related to the increase in HIFs production.
One of the most important consequences of
HIF hyper-secretion in neonates affected by
asphyxia is the increase in VEGF expression
[15]. At morphological level, the consequences
of VEGF hyperexpression could be summarized
as follows: i) endothelial swelling, probably
representing the first physiological response of
endothelial cells to VEGF hyper-secretion; ii)
endothelial exhaustion, consequent to a persistent
and pathological hyper-stimulation by VEGF,
followed by endothelial cell death by apoptosis;
iii) enlargement of the inter-endothelial tight
junctions, followed by endothelial detachment;
iiii) loss of the endothelial barrier. These
histological changes are all easily recognized at
histology, and may be observed both in arteries
and in veins (Fig. 2). The consequences of the loss
of the endothelial barrier are multiple and, taken
together, may explain the vast majority of lesions
in multiple organs observed in the clinical setting
of perinatal asphyxia, occasionally leading to
multiple organ failure [16]. At histology, the loss
of the endothelial barrier is generally associated
with the following lesions.
Figure 1. Endothelial disfunction in hypoxic acute injury.
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Figure 2. Summary of histological changes in arteries and in veins.
a. Diffuse intravascular coagulation (DIC),
characterized by the presence of thrombi in
the lumen of blood vessels, mainly affecting
arteries and veins in which endothelium is
absent (Fig. 3).
b. Edema of the perivascular tissues, due to the
leakage of liquid and proteins related to the
loss of the physiological selective barrier
represented by the endothelial cells (Fig. 4).
c. Loss of the microvascular reactivity, in part
related to the endothelial cells, leading to
persistent dilatation of the affected vessels.
d. Perivascular hemorrhages, due to a severe
disruption of the vascular wall.
e. Dysfunction of the neurovascular brain unit,
followed by dysfunction of the brain blood
barrier, leading to perivascular edema and
neuronal cell death [17] (Fig. 5). Recently, the
use of immunohistochemistry for albumin has
been suggested as a useful tool for detecting
the pathological changes of the blood brain
barrier in neonates affected by perinatal
asphyxia [18].
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Liver
The finding of increased hepatic hemopoiesis
represents one of the most important markers of
chronic tissue hypoxia.
Erythropoiesis is a dynamic process regulated
through complex interplay of cytokines, nutrient
availability, and the cellular environment of
erythroid precursors [19] (Fig. 6). Critical factors
governing red cell formation include oxygen and
iron sensing, which act through the transcription
factor hypoxia-inducible factor-2α (HIF-2α)
[20]. Intestinal HIF-2s have been shown to be
essential for iron absorption, HIF-2α promoting
duodenal iron absorption following iron deficiency
[21]. Moreover, HIF-2α plays a central role in
erythropoiesis and hematopoietic development by
regulating EPO expression [22]. In preterm babies
with birth weight < 1.0 kg (commonly designated
as extremely low birth weight, or ELBW, infants)
affected by anemia, the hemoglobin levels are lower
than in term infants, due to diminished plasma EPO
levels in response to anemia. Erythroid progenitor
Figure 3. Thrombosis.
Figure 4. Edema.
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Figure 5. Perivascular edema.
Figure 6. Hepatic hemopoiesis.
6/11
cells of newborn infants are quite responsive to
EPO in vitro – a finding suggesting that inadequate
production of EPO is one major cause of neonatal
anemia, and not marrow unresponsiveness [23]. The
iron regulatory protein 1 (IRP1) has been recently
shown to play a role in the control of hemopoiesis,
by inhibiting mRNA translation of HIF-2α, with
which it forms a regulatory axis that coordinates
iron and oxygen sensing with erythropoiesis [24]
(Fig. 2). During gestation, hematopoietic stem
cells develop from the mesodermal germ layer and
successfully localize to two independent anatomical
sites, the yolk sac and the dorsal aorta. Subsequently,
hematopoietic cell populate the fetal liver, that
represent the principal source of blood cells during
the intrauterine life [25, 26]. Recent studies indicate
that EPO is a critical regulator of multiple aspects of
erythroid precursors during primitive and definitive
erythropoiesis, including cell survival, proliferation
and the rate of terminal maturation [27].
All these data, summarized in Fig. 7, clearly
indicate the utility of a deep analysis of the degree
of liver hemopoiesis in the pathological evaluation
of perinatal asphyxia. Higher the degree of
hemopoiesis, higher the level of tissue hypoxia.
In case of absence of morphological evidences
of hepatic hemopoiesis, particularly in preterm
infants, caution should be taken in performing a
certain pathological diagnosis of perinatal asphyxia,
and other etiologies other than hypoxia should be
considered.
Since HIFs have been shown to interfere on the
expression of hepcidin in liver cells, by decreasing
its production [28], immunohistochemistry for
hepcidin should be mandatory in all cases of
perinatal asphyxia, in order to better correlate the
clinical picture with the consequences of hypoxia at
molecular level.
Lungs
Vascular changes probably represent the most
frequent lesions observed at histological level
in newborns affected by asphyxia. Congestion,
i.e. dilatation of alveolar capillaries, arteries
and veins, is the most frequent change observed
at histological level in lung specimens of
asphyxiated neonates, capillary and arteriolar
dilatation representing the loss of vascular
reactivity due to hypercapnia [14]. Pulmonary
Figure 7. Erytropoiesis in hypoxia. EPO: erythropoietin; HIF-2α: hypoxia-inducible factor-2α.
7/11
hemorrhage is the other histological change often
observed in the setting of asphyxia, following
a more severe disruption of the vascular unit
[29]. Birth asphyxia has been shown to be
associated with increased pulmonary vascular
resistance (PVR), due to the absence of the
physiological increase of oxygen tension at birth
that represents an important factor in decreasing
PVR after delivery [30]. As a consequence, the
presence of pulmonary arterioles with the typical
“fetal appearance”, characterized by a thick
muscular wall and a narrow lumen, should be
always verified, in order to verify if pulmonary
hypertension has been caused by the persistence
of fetal arteries or by other factors.
Brain
Assuming that HIE represents the most important
clinical consequence of perinatal asphyxia [31],
brain lesions have been reported in many studies.
The most important histological changes are
summarized in Fig. 8.
a. Pial arteriolar vasodilatation is a constant finding
in the brain of asphyxiated newborns. It is simply
evidenced at panoramic view, and it is mainly
related to the loss of microvascular reactivity in
cerebral vessels [14].
b. Endothelial damage represents probably the most
important change in the brain of asphyxiated
newborns. All the endothelial lesions previously
reported may be encountered at the histological
examination of brain samples. Endothelial
swelling represents a peculiar feature in the small
intracerebral vessels. Given the narrow lumen of
the intravascular capillaries, endothelial swelling
may lead to the occlusion of the vascular
lumen, leading to the block of the intracerebral
circulation, aggravating brain hypoxia.
c. The endothelial damage is followed by the dysfunction of the neurovascular unit that contributes
to subsequent neuronal cell death [17].
d. Neuronal cell death represents a major
pathological finding in the interpretation of
the severity of the hypoxic encephalopathy.
Apoptosis is the most frequent type of cell death
occurring in the brain of asphyxiated newborns.
At histology, affected neurons show shrinkage,
increased eosinophylia of the cytoplasm,
nuclear piknosis and kariorexis, ending with the
formation of roundish eosinophilic globules that
appear intermingled with preserved neurons.
Figure 8. Brain damage in hypoxic-ischemic encephalopathy.
8/11
Neuronal apoptosis may be encountered, in the
clinical setting of asphyxia, in all the cerebral
regions. In our experience, neurons of the brain
stem, basal nuclei and cerebellum appear as the
most frequently affected by apoptosis, often in
association with apoptosis of the cerebral cortical
neurons. Recently, the increased expression of proapoptotic proteins – including BAX, cytoplasmic
cytochrome C and caspase-3 – has been reported
in the cortex and thalamus of the brain of mice
affected by birth hypoxia [32], suggesting the use
of these antibodies in cases in which histology
could not clearly evidence the typical features
of neuronal cell death. The hippocampus should
be always sampled for histological studies,
given the frequent functional compromise of this
brain region in newborns affected by asphyxia,
particularly in female infants [33]. In a recent
study, all 16 full-term asphyxiated infants
displayed neuronal cell damage and glial reactivity
in the hippocampus. In the same study, a strong
immunreactivity for acquaporin was detected on
hippocampal astrocytes in 50% of patients [18],
suggesting the use of this immunohistochemical
reaction in all newborns with a clinical history of
perinatal asphyxia.
Kidneys
Acute kidney injury (AKI) has been reported
in variable percentages, up to 56%, of newborns
affected by perinatal asphyxia [34]. The prevalence
of AKI is about three fold higher in neonates with
birth weight lower than 1,500 g [35]. At histology,
AKI is characterized by prevalent changes in
tubular epithelial cells, proximal tubular cells
representing the main target of hypoxia [36] (Fig.
9). At histology, proximal tubular cells show all the
morphological markers of apoptosis: detachment
from neighboring cells; increased eosinophilia of
their cytoplasm; condensation of the chromatin;
fragmentation of the nucleus; detachment from the
basal lamina; aggregation into the tubular lumen,
giving rise to cellular casts.
Figure 9. Hypoxic-ischemic damage in preterms.
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Thyroid gland
Alterations in thyroid metabolism in newborns
have been first described about 30 years ago,
asphyxiated neonates being characterized by the
absence of the increase of FT4 and FT3 serum
levels in the perinatal period [37]. Further studies
evidenced the occurrence of hypothyroidism in
newborns with HIE, the involvement of the thyroid
gland representing a greater risk of death in these
patients [38]. Even though, at the best of our
knowledge, no histological study has been carried
out on thyroid histology in asphyxiated newborns,
these data taken together induce to suggest a careful
histological examination of the thyroid gland in
every case of perinatal asphyxia.
Discussion
Given the practical aim of this work, mainly
focused on giving a simple check list of the
histological lesions pathologists should look for
in the autopsy of a newborn affected by asphyxia,
the last part of our work is dedicated to this aim.
In Tab. 1 all the most relevant histological lesions
here described are reported.
Table 1. Main histological changes related to perinatal
hypoxia.
1. Blood vessels
Endothelial swelling
Endothelial detachment
Loss of the endothelial barrier
Perivascular edema
Intravascular coagulation
Among them, we want to lay stress on the
endothelial lesions that, in our opinion, represent
the most relevant pathological changes induced
by hypoxia in all the organs. The progressive
morphological changes representing endothelial
dysfunctions related to tissue hypoxia are, probably,
at the basis of the most relevant consequences in the
different tissues: edema and thrombosis. The former
dissociates the multiple cell types of different organs,
with complex and severe consequences of their
function; the latter aggravates hypoxia in affected
tissues, mainly in cases in which disseminated
intravascular coagulation occurs. All these data taken
together, induce to a better analysis of blood vessels
and, in particular, of endothelial cells, looking for the
morphological markers of endothelial dysfunction.
Starting with endothelial swelling that, particularly
in the small capillaries of the brain, due to their
narrow lumen, may represent a mechanical block to
red blood cell circulation, leading to the aggravation
of the hypoxic state, ending with neuronal cell death.
In conclusion, the accurate histological study of
all the organs in every case of perinatal asphyxia may
allow perinatal pathologists to give important data
to neonatologists for reaching, together, a complex
clinical/pathological diagnosis, able to explain
the clinical course in the majority of asphyxiated
newborns undergoing multiple organ dysfunction.
Declaration of interest
The Authors declare that there is no conflict of interest.
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3. Lungs
Interstitial edema
Interstitial hemorrhage
Alveolar capillary dilatation and congestion
4. Heart
Coronary vessel congestion
Coronary vessel thrombosis
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Histological markers of neonatal asphyxia

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